Process for producing α-aminoketones

ABSTRACT

A process for producing α-aminohalomethyl ketones or N-protected α-aminohalomethyl ketones from specified 3-oxazolidin-5-one derivatives via 5-halomethyl-5-hydroxy-3-oxazolidine derivatives. By this process, α-aminohalomethyl ketones and compounds relating to them can be obtained efficiently and economically in industrial scale.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a Divisional application of U.S. Ser. No.10/290,266 filed on Nov. 8, 2002 now U.S. Pat. No. 6,696,571, which is aDivisional application of U.S. Ser. No. 09/943,361 filed on Aug. 31,2001, now U.S. Pat. No. 6,570,039, which is a Continuation applicationof PCT/JP00/01336 filed on Mar. 6. 2000.

BACKGROUND OF THE INVENTION

The present invention relates to a process for producingα-aminohalomethyl ketones or N-protected α-aminohalomethyl ketones fromspecified 3-oxazolidin-5-one derivatives via5-halomethyl-5-hydroxy-3-oxazolidine derivatives.

The present invention also relates to a process for producingβ-aminoalcohols, N-protected β-aminoalcohols or N-protectedβ-aminoepoxides from the α-aminohalomethyl ketones or N-protectedα-aminohalomethyl ketones.

The α-aminohalomethyl ketones and salts thereof can be converted intopeptidylhalomethyl ketones by a method usually employed in peptidesynthesis. These α-aminohalomethyl ketones and salts thereof are usefulas intermediates for synthesizing various peptidylhalomethyl ketonesknown as serine protease inhibitors (see, for example, W. Brandt et al.,Int. J. Peptide Protein Res. 46, 1995, 73).

It was reported that the α-aminohalomethyl ketones and salts thereof arealso useful as intermediates for synthesizing HIV protease inhibitors(see, for example, J. Med. Chem. 1990, 33, 1285).

It is also known that N-protected α-aminohalomethyl ketones,β-aminoalcohols as well as N-protected β-aminoalcohols and N-protectedβ-aminoepoxides derived from them are also known to be importantintermediates for HIV protease inhibitors. α-Aminohalomethyl ketoneswere produced by removing a protecting group from N-protectedα-aminohalomethyl ketones (see, for example, S. Fittkau et al., J.Prakt. Chem. 1986, 529).

For the production of N-protected α-aminohalomethyl ketones, forexample, there is known a process wherein an amino acid ester in whichthe amino group is protected is reacted with a metal enolate obtainedfrom an α-haloacetic acid and a resulting product is followed bydecarboxylation (WO 96/23756).

However, in this process, about 4 equivalents or more of an expensiveGrignard reagent or organic lithium reagent is necessitated for 1equivalent of the N-protected amino acid ester as shown in Examples inWO 96/23756.

Further, a process wherein an alanine ester in which the amino group isprotected with dibenzyl group is reacted with a halomethyllithium isknown (see J. Barluenga et al., J. Chem. Soc., Chem. Commun. 1994, 969).

However, only dibenzyl group is discussed as the protective group forthe amino group in this process, and no other protective group isdescribed therein. In addition, because no process is known for removingthe protecting group from the dibenzyl group while the halogenatedketone group is kept, the process of J. Barluenga et al. cannot beemployed for the production of α-aminohalomethyl ketones.

There is also known another process wherein a carbamato part of an aminoacid ester in which the amino group is protected with the carbamatogroup is further protected with a trialkylsilyl group and then thiscompound is reacted with a halomethyllithium (J. P. KOKAI Nos. Hei8-99947 and Hei 8-99959).

However, also in this process, about 2.2 equivalents of an expensiveorganic lithium reagent is necessitated for 1 equivalent of theN-protected amino acid ester as described in Examples in J. P. KOKAINos. Hei 8-99947 and Hei 8-99959. Although the protecting group for theamino group used in these Examples is only methoxycarbonyl group, noprocess for removing the methoxycarbonyl group while keeping thehalogenated ketone group is known yet. It is not yet proved that thisprocess can be employed for the production of α-aminohalomethyl ketones.

DISCLOSURE OF THE INVENTION

The object of the present invention is to provide an economical,efficient process for producing α-aminohalomethyl ketones and relatedcompounds on an industrial scale.

After intensive investigations made for the purpose of solving theabove-described problems, the inventors have found thatα-aminohalomethyl ketones or N-protected α-aminohalomethyl ketones canbe obtained in a high yield by reacting a 3-oxazolidin-5-one derivativewith a halomethyllithium to form a 5-halomethyl-5-hydroxy-3-oxazolidinederivative and treating this derivative with an acid.

Namely, the present invention provides a process for producingN-protected α-aminohalomethyl ketones of following general formula (3):

wherein A represents an unsubstituted or substituted alkyl group having1 to 10 carbon atoms, aryl group having 6 to 15 carbon atoms or aurallygroup having 7 to 20 carbon atoms, or a group corressponding theretowhich contains a hetero atom in the carbon skeleton; B¹ represents aprotecting group for the amino group; and X represents a halogen atom,α-aminohalomethyl ketones of following general formula (4):

wherein A and X are as defined above, or salts thereof, which comprisesthe steps of reacting a 3-oxazolidin-5-one derivative of followinggeneral formula (1):

wherein R represents an unsubstituted or substituted aryl group or loweralkyl group or hydrogen atom, and A and B¹ are as defined above with ahalomethyllithium and then treating the reaction product with an acid.

The present invention also provides 5-halomethyl-5-hydroxy-3-oxazolidinederivatives of following general formula (2):

wherein R represents an unsubstituted or substituted aryl group or loweralkyl group or hydrogen atom, A represents an unsubstituted orsubstituted alkyl group having 1 to 10 carbon atoms, aryl group having 6to 15 carbon atoms or aralkyl group having 7 to 20 carbon atoms, or agroup corresponding thereto which contains a hetero atom in the carbonskeleton; B¹ represents a protecting group for the amino group; and Xrepresents a halogen atom.

The present invention further provides 3-oxazolidin-5-one derivatives offollowing general formula (16)

wherein R represents an unsubstituted or substituted aryl group or loweralkyl group or hydrogen atom, and B¹ represents a protecting group forthe amino group.

BEST MODE FOR CARRYING OUT THE INVENTION

In the formulae in the present invention, R represents an unsubstitutedor substituted aryl group or lower alkyl group or hydrogen atom. Whenthose groups have a substituent, the substituent is an alkoxyl group,nitro group, an alkyl group, a halogen atom or the like. The aryl groupis preferably phenyl group which may have a substituent. The lower alkylgroups are preferably straight or branched, saturated alkyl groupshaving 1 to 4 carbon atoms.

A in the formulae in the present invention represents hydrogen atom, anunsubstituted or substituted alkyl group having 1 to 10 carbon atoms,aryl group having 6 to 15 carbon atoms or aralkyl group having 7 to 20carbon atoms, or a group corresponding thereto which contains a heteroatom in the carbon skeleton. When those groups have a substituent, thesubstituent is an alkoxyl group, nitro group, an alkyl group, a halogenatom or the like.

Such a group can be introduced into the compound from, e.g., an aminoacid. For example, when A is hydrogen atom, it can be introduced byusing glycine as the starting material. In the same way, methyl groupcan be introduced by using alanine; isopropyl group can be introduced byusing valine; 2-methylpropyl group can be introduced by using leucine;1-methylpropyl group can be introduced by using isoleucine; benzyl groupcan be introduced by using phenylalanine; and methylthioethyl group canbe introduced by using methionine.

A may be a group introduced by using an amino acid in which a functionalgroup in a side chain thereof is protected, such as S-t-butylcysteine,S-tritylcysteine, S-(p-methylbenzyl)cysteine,S-(p-methoxybenzyl)cysteine, O-t-butylserine, O-benzylserine,O-t-butylthreonine, O-benzylthreonine, O-t-butyltyrosine orO-benzyltyrosine, as the starting material.

A is not limited to a group introduced from a starting material derivedfrom a natural amino acid, but it may a group introduced from a startingmaterial derived from a synthetic amino acid (such as phenylthiomethylgroup). A is preferably benzyl group or phenylthiomethyl group.

X in the formulae in the present invention represents a halogen atom.The halogen atoms include fluorine atom, chlorine atom, bromine atom andiodine atom. In these atoms, chlorine atom or bromine atom is preferred.Chlorine atom is particularly preferred.

In the formulae in the present invention, B¹, B² and B³, independentlyfrom each other, represent a protecting group for amino group. Theprotecting group for amino group is not particularly limited. Forexample, protecting groups described in Protecting Groups in OrganicChemistry, 2^(nd) edition (John Wiley & Sons, Inc., 1991) are usable.Among them, carbamato-type protecting groups are preferred because theycan be easily removed. Examples of the carbamato type protecting groupsinclude methoxycarbonyl group, ethoxycarbonyl group, t-butoxycarbonylgroup, benzyloxycarbonyl group, fluorenylmethoxycarbonyl group andtetrahydrofuran-3-yloxycarbonyl group. Those protecting groups are notalways removed and they may be used also as they are in the subsequentstep depending on the intended compound in some cases. Examples of suchgroups include tetrahydrofuran-3-yloxycarbonyl group (European PatentNo. 774453) and 3-protected hydroxy-2-methylbenzoyl group.

3-Oxazolidin-5-one derivatives represented by general formula (1) in thepresent invention can be easily produced by a known method such as i) amethod wherein an N-protected amino acid is reacted with an aldehyde inthe presence of an acid (see, for example, S. I. Hyun et al.,Tetrahedron Lett. 1998, 39, 4299, and S. Karady et al., TetrahedronLett. 1984, 25, 39, 4337) or ii) a method wherein an α-amino acid or asalt thereof is reacted with an aldehyde and then the product is reactedwith a reagent for protecting the amino group (see, for example, M. W.Walter et al., J. Org. Chem. 1998, 63, 5179 and M. W. Walter et al.,Tetrahedron Lett. 1995, 36, 42, 7761).

The aldehydes are, for example, those of following general formula (6):R—CHO  (6)wherein R represents hydrogen atom, a lower alkyl group having 1 to 6carbon atoms or an aryl group having 6 to 15 carbon atoms.

Aldehydes preferably used in method i) include formaldehyde, loweralkylaldehydes such as acetaldehyde, and arylaldehydes such asbenzaldehyde and anisaldehyde. Formaldehyde is particularly preferred.The acids used for the reaction are preferably organic acids such asbenzenesulfonic acid, p-toluenesulfonic acid and pyridinep-toluenesulfonate (PPTS). The reaction solvents are preferably aproticsolvents such as benzene, toluene, tetrahydrofuran, dichloroethane,ethyl acetate and isopropyl acetate. Benzene or toluene is particularlypreferred.

The aldehydes preferably used in method ii) are formaldehyde, loweralkyl aldehydes such as acetaldehyde and trimethylacetaldehyde, andarylaldehydes such as benzaldehyde and anisaldehyde.

Examples of the amino group-protecting reagents includealkoxycarbonylating reagents such as methoxycarbonyl chloride,ethoxycarbonyl chloride, isopropoxycarbonyl chloride, t-butoxycarbonylchloride, benzyloxycarbonyl chloride, di-t-butyl dicarbonate andtetrahydrofuran-3-yloxycarbonyl chloride; acylating reagents such asacetic anhydride, acetyl chloride, benzoyl chloride and 3-protectedhydroxy-2-methylbenzoyl chloride; and sulfonylating reagents such asmethanesulfonyl chloride, trifluoromethanesulfonyl chloride,benzenesulfonyl chloride and p-toluenesulfonyl chloride.

The production process of the present invention can be employed forsynthesizing optically active compounds by using an optically activeα-amino acid or N-protected α-amino acid. Optically active amino acidsare important in the field of medicines. Namely, optically activecompounds (L- and D-compounds) are preferably used as the α-amino acidsand N-protected α-amino acids. In particular, optically activephenylalanine and optically active phenylthioalanine and N-protectedcompounds of them are important starting materials of HIV proteaseinhibitors.

Now, the description will be made on the process for producing5-chloromethyl-5-hydroxy-3-oxazolidine derivatives of general formula(2) by reacting a 3-oxazolidin-5-one derivative of general formula (1)with a lower alkyllithium and bromochloromethane or chloroiodomethane.

Halomethyllithiums in the present invention can be represented byfollowing general formula (17):Li—CH₂—X  (17)wherein X is as defined above.

These halomethyllithiums can be formed by reacting an organic lithiumcompound such as methyllithium, n-butyllithium or sec-butyllithium witha dihalomethane such as bromochloromethane, chloroiodomethane ordibromomethane [see, for example, Encyclopedia of reagents for organicsynthesis (John Wiley & Sons, Inc., 1995)]. A halomethyl ketone can beobtained by reacting a halomethyllithium, obtained as described above,with an ester (see, for example, R. Tarhouni et al., tetrahedron Lett.1984, 25, 835; and J. Barluenga et al., J. Chem. Soc., Chem. Commun.1994, 969). Also in the present invention, an organic lithium compoundand a dihalomethane are added to a reaction solvent to form acorresponding halomethyllithium in the reaction system.

The halomethyllithiums are preferably chloromethyllithium andbromomethyllithium. Chloromethyllithium is particularly preferred.Chloromethyllithium is formed in the production of α-aminochloromethylketone [general formula (3) or (4) wherein X is chlorine atom], andbromomethyllithium is formed in the production of α-aminobromomethylketone [general formula (3) or (4) wherein X is bromine atom].

As known in the art, the halomethyllithiums are thermally unstable and,therefore, when a halomethyllithium is to be reacted with an ester, itis preferred to previously dissolve the ester and the dihalomethane in asolvent and then to add an organic lithium compound. The reaction may beconducted in the presence of a salt such as lithium chloride or lithiumbromide.

The organic lithium compounds used in the present invention can berepresented by, for example, following general formula (18):R¹—Li  (18)wherein R¹ represents a lower alkyl group or aryl group.

The lower alkyl groups include linear or branched, saturated alkylgroups having 1 to 8 carbon atoms, and the aryl groups include phenylgroup, naphthyl group, etc. Lower alkyllithiums of the above formulawherein R¹ represents a lower alkyl group are preferred. In particular,lower alkyllithiums of the above formula wherein R¹ represents a linear,saturated alkyl group having 1 to 6 carbon atoms such as methyl group,ethyl group, n-butyl group, sec-butyl group or n-hexyl group arepreferred.

The dihalomethanes usable in the present invention are preferablybromochloromethane, chloroiodomethane and dibromomethane.Bromochloromethane and chloroiodomethane are particularly preferred.Bromochloromethane or chloroiodomethane is used for the production ofα-aminochloromethyl ketone [general formula (3) wherein X representschlorine atom] (when chloromethyllithium is formed). Dibromomethane isused for the production of α-aminobromomethyl ketone [general formula(3) or (4) wherein X represents bromine atom] (when bromomethyllithiumis formed).

The amount of the organic lithium compound and dihalomethane used is notparticularly limited, and they are used each in an amount of 1 to 2equivalents per equivalent of the N-protected α-amino acid esterderivative. Although the amount of them may be larger than 2equivalents, it is preferably 1 to 1.5 equivalents and more preferably1.2 to 1.4 equivalents in the present invention because these reagentsare expensive.

The reaction solvents are preferably ethers such as tetrahydrofuran,diethyl ether and t-butyl methyl ether. They are preferably used in theform of a mixture with a non-polar solvent such as toluene or hexane.The reaction rapidly proceeds at a temperature ranging from about −120°C. to 0° C. Usually, the reaction is completed in 5 to 60 minutes at−80° C. to −50° C. After the completion of the reaction, the reactionmixture may be treated with an aqueous potassium hydrogensulfatesolution, aqueous ammonium chloride solution, phosphate buffer, water orthe like. By treating the reaction mixture with an acid, the hydrolysisreaction in the subsequent step can be directly conducted.

Although the 5-halomethyl-5-hydroxy-3-oxazolidine derivative thusobtained can be purified by a method known in the art such as columnchromatography, it may be used for the subsequent reaction without beingseparated or purified. When this compound is used for the production ofcompounds of general formula (3) or (4), the separation or purificationthereof is usually not required.

A 3-oxazolidin-5-one derivative of general formula (1) is reacted with ahalomethyllithium to obtain a 5-chloromethyl-5-hydroxy-3-oxazolidinederivative of general formula (2):

wherein X represents a halogen atom, and R, A and B¹ are as definedabove.

Then, the description will be made on the process for producing anN-protected α-aminohalomethyl ketone of general formula (3) or anα-aminohalomethyl ketone of general formula (4) or a salt thereof bytreating a 5-halomethyl-5-hydroxy-3-oxazolidine derivative of generalformula (2) with an acid.

5-Halomethyl-5-hydroxy-3-oxazolidine derivatives of general formula (2)can be hydrolyzed by the reaction with an acid. The protecting group forthe amino group is either removed or not removed depending on therelationship between the reaction conditions and the protecting groupfor the amino group.

The acids are not particularly limited, and they include inorganic acidssuch as hydrochloric acid, hydrobromic acid, hydroiodic acid andsulfuric acid; and organic acids such as formic acid, acetic acid andtrifluoroacetic acid, and a combination of, for example, hydrobromicacid/acetic acid.

The solvents are not particularly limited, and they include water,methanol, ethanol, tetrahydrofuran, dioxane, ethyl acetate,dichloromethane, chloroform, toluene, hexane or a mixture of thesesolvents.

The N-protected α-aminohalomethyl ketone obtained when the protectinggroup for the amino group was not removed can be used after thepurification by a method known in the art such as column chromatographyor it can also be used for the subsequent reaction without theseparation or purification.

The α-aminohalomethyl ketone obtained when the protecting group wasremoved can be converted to its salt by evaporating the solvent andcrystallizing it under proper conditions. Various salts of theα-aminohalomethyl ketone can be obtained depending on the variety of theacid used. These salts can be used for the subsequent reaction as theyare in the present invention. The salt can be converted to a freecompound by the reaction with a corresponding amount of a base. However,the acidic salt is preferably used as it is because the free compound ismore unstable than the salt.

When, for example, a 5-halomethyl-5-hydroxy-3-oxazolidine derivative ishydrolyzed with water or a water-containing solvent mixture (including acase wherein a reaction solution containing the5-halomethyl-5-hydroxy-3-oxazolidine derivative is treated with an acidto directly conduct the hydrolysis reaction) and the alkoxycarbonylationreaction (such as methoxycarbonylation, ethoxycarbonylation,t-butoxycarbonylation or benzyloxycarbonylation reaction) of anα-aminohalomethyl ketone or reduction reaction of carbonyl group can beconducted in an aqueous solvent, the α-aminohalomethyl ketone solutioncan be directly used in the subsequent step.

Thus obtained N-protected α-aminohalomethyl ketone of general formula(3) or α-aminohalomethyl ketone of general formula (4) can be convertedinto an N-protected β-aminoepoxide by any of following reaction schemes(A), (B) and (C):

wherein A, B¹, B², B³ and X are as defined above.

N-Protected-α-aminohalomethyl ketones of general formula (3) are knowncompounds usable as intermediates for HIV protease inhibitors (see, forexample, D. P. Getman et al., J. Med. Chem., 1993, 36, 288; Y. Okada etal., Chem. Pharm. Bull., 1988, 36, 4794; EP 346867; and P. Raddatz etal., J. Med. Chem., 1991, 34, 3267). It is known that they can beconverted into intermediates closer to the intended final product by twosteps of known reactions as described below (see D. P. Getman et al., J.Med. Chem., 1993, 36, 288; WO 96/23756, J. P. KOKAI No. Hei 8-99947 andJ. P. KOKAI No. Hei 8-99959).

Namely, an N-protected-α-aminohalomethyl ketone of general formula (3)can be converted into an N-protected-β-amino alcohol of general formula(8) by the reduction reaction of the carbonyl group, and then thealcohol can be then easily epoxidized under an alkaline condition toform an N-protected-β-amino epoxide of general formula (9).

The description will be made on the process for protecting amino groupof an α-aminohalomethyl ketone of general formula (4) with a protectinggroup to form an N-protected-α-aminohalomethyl ketone of general formula(10).

Although α-aminohalomethyl ketones are stable under acidic conditions,they are unstable under basic conditions. Therefore, it is not preferredto conduct the reaction under basic conditions which are usuallyemployed for the reaction for protecting the amino group in thesynthesis of peptides.

Namely, reagents for protecting amino group such as alkoxycarbonylatingreagents, acylating reagents and sulfonylating reagents must be used inthe presence of a base. In the course of the reaction of them, theα-aminohalomethyl ketone is decomposed in a considerable amount toreduce the reaction yield. Therefore, for the efficient protection, theamino acid is preferably protected as follows:

-   Method 1: A reagent for protecting the amino group, such as an    alkoxycarbonylating reagent, an acylating reagent or a sulfonylating    reagent, is mixed with a base in a suitable solvent, and then a    solution of an acidic salt of an α-aminohalomethyl ketone is added    to the obtained mixture.-   Method 2: A solution of a reagent for protecting the amino group,    such as an alkoxycarbonylating reagent, an acylating reagent or a    sulfonylating reagent, is mixed with a solution of an acidic salt of    α-aminohalomethyl ketone, and then a base is added to the obtained    mixture.

Particularly in the t-butoxycarbonylation, method 1 is preferred becauset-butoxycarbonyl chloride or di-t-butyl dicarbonate used as theprotecting reagent is unstable to acids.

Reagents for protecting amino group are not particularly limited. Thereagents usable herein are not only those usually used for synthesizingpeptides but also compounds having a functional group such as analkoxycarbonyl group, an acyl group or sulfonyl group are usable forintroducing an intended substituent.

Examples of the reagents for protecting amino group includealkoxycarbonylating reagents such as methoxycarbonyl chloride,ethoxycarbonyl chloride, isopropoxycarbonyl chloride, t-butoxycarbonylchloride, benzyloxycarbonyl chloride, di-t-butyl dicarbonate andtetrahydrofuran-3-yloxycarbonyl chloride; acylating reagents such asacetic anhydride, acetyl chloride, benzoyl chloride and 3-protectedhydroxy-2-methylbenzoyl chloride; and sulfonylating reagents such asmethanesulfonyl chloride, trifluoromethanesulfonyl chloride,benzenesulfonyl chloride and p-toluenesulfonyl chloride. The protectinggroups introduced by using those protecting reagents are not alwaysremoved, and they may the kept depending on the subsequent reactionsteps and intended compounds.

The reaction solvents are, for example, water, methanol, ethanol,2-propanol, t-butanol, acetone, tetrahydrofuran, diethyl ether, t-butylmethyl ether, ethyl acetate, isopropyl acetate, dichloromethane,chloroform and toluene, and mixtures of them. The solvent can besuitably selected depending on the reagent. When a solvent mixture isused, the mixture is either mono-layered or di-layered depending on thecombination of the solvents. The reaction is preferably conducted in thedi-layered solvent.

The α-aminohalomethyl ketones are preferably in the form of stableacidic salts thereof as described above. The solvents in which theacidic salts are to be dissolved are, for example, water, methanol andethanol.

The α-aminohalomethyl ketone solution is added to the solvent containingthe protecting reagent dissolved therein. The reaction time variesdepending on the reagent and reaction temperature. In a typical examplewherein di-t-butyl dicarbonate is used for the t-butylcarbonylation, thereaction is completed in several minutes to about 2 hours at 40° C. orin several minutes to about 10 hours at room temperature.

The bases are organic bases such as triethylamine,diisopropylethylamine, dicyclohexylmethylamine, N-methylmorpholine,N-ethylmorpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, 4-picolineand N-ethylpiperidine; and inorganic bases such as sodium hydroxide,potassium hydroxide, sodium carbonate, potassium carbonate, sodiumhydrogencarbonate, potassium hydrogencarbonate, disodiumhydrogenphosphate and dipotassium hydrogenphosphate.

When the reagent for protecting amino group is mixed with the base in asuitable solvent and then a solution of an acidic salt ofα-aminohalomethyl ketone is added to the solution (method 1 describedabove), the base is preferably sodium hydrogencarbonate, potassiumhydrogencarbonate, triethylamine or diisopropylethylamine. The base isparticularly preferably triethylamine or diisopropylethylamine. Theamount of the base to be added to the solution of the protecting reagentis preferably 0.8 to 1.2 equivalents, more preferably around 1equivalent, per equivalent of the acid (including the acid used forforming the salt) contained in the solution of the acidic salt ofα-aminohalomethyl ketone.

The α-aminohalomethyl ketone solution is added to the solvent containingthe protecting reagent dissolved therein. The reaction time variesdepending on the reagent and reaction temperature. For example, whendi-t-butyl dicarbonate is used for the t-butylcarbonylation, thereaction is completed in several minutes to about 2 hours at 40° C. orin several minutes to about 10 hours at room temperature.

When a solution of a reagent for protecting the amino group, such as analkoxycarbonylating reagent, an acylating reagent or a sulfonylatingreagent is mixed with a solution of an acidic salt of α-aminohalomethylketone and then a base is added to the obtained mixture (method 2described above), the base is preferably sodium hydrogencarbonate,potassium hydrogencarbonate, triethylamine or diisopropylethylamine. Theamount of the base to be added is preferably 0.8 to 1.2 equivalents,more preferably around 1 equivalent, per equivalent of the acid(including the acid used for forming the salt) contained in the solutionof the acidic salt of α-aminohalomethyl ketone.

The base is used in the form of a solution in a suitable solvent. Thereaction time varies depending on the reagent and reaction temperature.For example, when benzyloxycarbonyl chloride is used for thebenzyloxycarbonylation, the reaction is completed in about 10 minutes toabout 2 hours at room temperature.

Then the reaction product is extracted from the reaction solution with asolvent such as ethyl acetate, diethyl ether, toluene, isopropylacetate, tert-butyl methyl ether, dichloromethane or chloroform. Then,ifnecessary, the obtained solution is concentrated (or evaporated). Ifnecessary, a solvent such as methanol, ethanol, 2-propanol,acetonitrile, tetrahydrofuran, hexane, heptane or acetone is added tothe product. The obtained solution is heated to about 40 to 80° C. TheN-protected α-aminohalomethyl ketone (7) can be obtained in solid formby the crystallization by cooling to a temperature of −20° C. to roomtemperature or by a chromatography. The product may be used for thesubsequent reaction without being separated or purified.

The solvent containing the protecting reagent dissolved therein containsa base in an amount of preferably 0.8 to 1.2 equivalents, morepreferably around 1 equivalent, per equivalent of the acid contained inthe solution of the acidic salt of α-aminohalomethyl ketone.

As described above, an N-protected-α-aminohalomethyl ketone of generalformula (10) can be converted to an N-protected-β-amino alcohol ofgeneral formula (11) by the reduction reaction of the carbonyl group,and then the alcohol can be easily epoxidized under an alkalinecondition to form an N-protected-β-aminoepoxide of general formula (12).

The description will be made with reference to an example wherein sodiumborohydride is used as the reducing agent.

Although the amount of sodium borohydride to be added is notparticularly limited, it is usually used in an amount of at least 0.5mol per mol of the starting compound.

The reaction solvents are protic solvents such as water and alcohols.Alcohols or mixed solvents of an alcohol and at least one of othersolvents are preferred. The alcohols are, for example, methanol,ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol and1,2-dimethylpropanol. Methanol and ethanol are particularly preferred. Acombination of these alcohols is also usable. The solvents usable in theform of a mixture with the alcohols are, for example, ethyl acetate,isopropyl acetate, dichloromethane, ether, tert-butyl methyl ether,tetrahydrofuran, 1,4-dioxane, benzene, toluene and water. Ethyl acetate,toluene and water are particularly preferred.

Although the reaction temperature is not particularly limited, it isusually not higher than room temperature and is preferably −78° C. toroom temperature, more preferably −78° C. to 5° C. The reaction time,which is also not particularly limited, is preferably about 10 minutesto 10 hours.

The reaction is usually conducted under stirring. After the completionof the reaction, the reaction is usually terminated with an acid. Theacids preferably used are hydrochloric acid, sulfuric acid, acetic acid,citric acid and an aqueous potassium hydrogensulfate solution. Althoughthe amount of the acid used is not particularly limited, it ispreferably at least 1 molar equivalent per molar equivalent of sodiumborohydride.

Then the reaction product is extracted from the reaction solution with asolvent such as ethyl acetate, diethyl ether, toluene, isopropylacetate, tert-butyl methyl ether, dichloromethane or chloroform. Ifnecessary, the obtained solution is concentrated (or evaporated). Ifnecessary, a solvent such as methanol, ethanol, 2-propanol,acetonitrile, tetrahydrofuran, hexane, heptane or acetone is addedthereto and the obtained solution is heated to about 40 to 80° C. andthen cooled to −20° C. to room temperature to conduct thecrystallization or the solution is subjected to a chromatography toobtain the N-protected β-aminoalcohol in solid form. CrystallineN-protected β-aminoalcohol can also be obtained by concentrating thereaction solution if necessary, adding water thereto if necessary,directly cooling the reaction solution under the above-describedconditions to form crystals and washing the obtained crystals with wateror an organic solvent.

An N-protected β-aminoepoxide of general formula (9) can be obtained bytreating the obtained N-protected β-aminoalcohol of general formula (8)with a base.

The bases are, for example, potassium hydroxide, sodium hydroxide,potassium carbonate, sodium carbonate, sodium methoxide, sodiumethoxide, potassium tert-butoxide and sodium hydride. Sodium hydroxideand potassium carbonate are particularly preferred. The reactionsolvents are protic solvents such as methanol, ethanol, 1-propanol,2-propanol, 1-butanol, 2-butanol, 1,2-dimethylpropanol and water andaprotic solvents such as acetone, tetrahydrofuran and acetonitrile. Theyare used either alone or in the form of a mixture of them. In thosesolvents, ethanol, a solvent mixture of 2-propanol and water and asolvent mixture of ethanol and water are particularly preferred.

The amount of the base, which varies depending on the combination of thebase and the solvent, is 1 to 10 equivalents, preferably 1 to 5equivalents. The reaction temperature which also varies depending on thecombination of the base and the solvent, is −10 to −80° C., preferably 0to −60° C. The reaction time, which is not particularly limited, ispreferably about 10 minutes to 50 hours.

The reaction is usually conducted under stirring. After the completionof the reaction, the reaction may be terminated with an acid. The acidspreferably used are hydrochloric acid, sulfuric acid, acetic acid,citric acid and an aqueous potassium hydrogensulfate solution.

Then the reaction product is extracted from the reaction solution with asolvent such as ethyl acetate, diethyl ether, toluene, isopropylacetate, tert-butyl methyl ether, dichloromethane or chloroform. Ifnecessary, the obtained solution is concentrated. If necessary, asolvent such as methanol, ethanol, 2-propanol, acetonitrile,tetrahydrofuran, hexane, heptane or acetone is added thereto and theobtained solution is heated, if necessary, to room temperature to about50° C. and then cooled to −20° C. to room temperature to conduct thecrystallization or it is subjected to a chromatography to obtain thesolid N-protected β-amino epoxide. Crystalline N-protected β-aminoepoxide can also be obtained by concentrating the reaction solution ifnecessary, adding water thereto if necessary, directly cooling thereaction solution under the above-described conditions to form crystalsand washing the obtained crystals with water or an organic solvent.

An α-aminohalomethyl ketone of general formula (4) can be converted intoa β-aminoalcohol of general formula (13) by reducing the carbonyl groupof the ketone. The concrete description will be given below.

A reducing agent is previously dissolved or suspended in a suitablesolvent, and then a solution of an acidic salt of the α-aminohalomethylketone is added thereto.

The solvent in which the reducing agent is to be dissolved or suspendedis not particularly limited. It is preferably a protic solvent such aswater, methanol or ethanol.

The solvent in which α-aminohalomethyl ketone is to be dissolved is, forexample, water, methanol or ethanol. The α-aminohalomethyl ketone ispreferably used in the form of a salt with an acid.

The reducing agent is not particularly limited. However, when thereaction is conducted in an aqueous solution, the reducing agent isparticularly preferably sodium borohydride or sodium cyanoborohydride.Although the amount of the reducing agent is not particularly limited,it is usually used in an amount of at least 0.5 molar equivalent permolar equivalent of the starting compound.

For inhibiting the decomposition of the reducing agent with the acid, itis preferred to add a base together with the reducing agent. The amountof the base to be added to the solution of the reducing agent ispreferably 1 to 2 equivalents, more preferably around 1 equivalent, perequivalent of the acid (including the acid used for forming the salt)contained in the solution of the acidic salt of α-aminohalomethylketone.

The bases are sodium hydroxide, potassium hydroxide, sodium carbonate,potassium carbonate, sodium hydrogencarbonate, potassiumhydrogencarbonate, etc.

The reaction temperature is not particularly limited. For example, whensodium borohydride is used, the reaction is conducted at a temperatureof preferably −20 to 100° C., particularly 0° C. to room temperature.

The reaction is usually conducted under stirring. After the completionof the reaction, the reaction is usually terminated with an acid. Theacids preferably used are hydrochloric acid, sulfuric acid, acetic acid,citric acid and an aqueous potassium hydrogensulfate solution. Althoughthe amount of the acid used is not particularly limited, it ispreferably at least 1 molar equivalent per molar equivalent of sodiumborohydride.

After adding water to the reaction mixture, the aqueous layer is washedwith a suitable organic solvent such as ethyl acetate, isopropylacetate, dichloromethane, chloroform or toluene to transfer an aldehydeand a ketone formed as by-products by the hydrolysis into the organiclayer. The obtained aqueous layer is concentrated. An alcohol is addedto the obtained concentrate, an insoluble matter is filtered out andthen product is crystallized under suitable conditions (e. g.crystallization by cooling or crystallization by concentration) from analcohol or a solvent mixture of the alcohol and one or more solvents toobtain the β-aminoalcohol in the form of a salt thereof. The alcoholsare, for example, methanol, ethanol and 2-propanol. The solvents usablein the form of a mixture with the alcohols are, for example, ethylacetate, isopropyl acetate, dichloromethane, diethyl ether, tert-butylmethyl ether, tetrahydrofuran, 1,4-dioxane, benzene, toluene and water.

β-Aminoalcohols of general formula (13) are well-known compounds usableas, for example, intermediates for HIV protease inhibitors (see, forexample, P. L. Beaulieu et al., J. Org. Chem., 1996, 61, 3635). It isknown that they can be converted into intermediates closer to theintended final product by two steps of known reactions as describedbelow.

Namely, β-aminoalcohols of general formula (13) are converted toN-protected β-aminoalcohols of general formula (14) by protecting theamino group of the former by an ordinary method. The N-protectedβ-aminoalcohols can be easily epoxidized under alkaline conditions toform N-protected β-aminoepoxides of general formula (15).

The compounds in the present invention also include racemic compoundsand both optically active compounds. When an N-protected α-amino acid ofgeneral formula (5) or an α-amino acid of general formula (7) is used, acompound of general formula (3) or (4) obtained by the process of thepresent invention maintains its optical activity. Further, compounds ofgeneral formulae (7) to (15) produced from the compounds of generalformula (3) or (4) also maintain their optical activity. Therefore, theprocess of the present invention is extremely useful for the synthesisof intermediate compounds for medicines.

The following Examples will further illustrate the present invention.

REFERENTIAL EXAMPLE 1 Process for Producing(4S)-N-tert-butoxycarbonyl-4-phenylmethyloxazolidin-5-one

Tert-butoxycarbonyl-L-phenylalanine (20.00 g), paraformaldehyde (6.04 g)and pyridinium p-toluenesulfonate (0.95 g) were added to toluene (200ml), and they were stirred under heating and reflux for 30 minutes. Thereaction mixture was cooled to room temperature and washed with asaturated aqueous sodium hydrogencarbonate solution and saturatedaqueous sodium chloride solution. The obtained toluene layer was driedover anhydrous sodium sulfate and then sodium sulfate was removed. Thesolvent was evaporated under reduced pressure. The concentrated solutionwas cooled to room temperature to crystallize the product. The crystalswere separated and dried to obtain intended(4S)-N-tert-butoxycarbonyl-4-phenylmethyloxazolidin-5-one (15.10 g)(yield: 72%).

1H-NMR(CDCl3, 300 MHz) δ ppm: 1.51 (9H, s), 3.15 (d, 1H), 3.20-3.52 (m,1H), 4.13-4.38 (m, 1H), 4.49 (bs, 1H), 5.06-5.38 (m, 1H), 7.12-7.22 (m,2H), 7.22-7.35 (m, 3H)

mass spectrum m/e: 278.2 (MH+)

[α]_(D) ²⁰=+153.4° (c=0.7, CH₂Cl₂)

REFERENTIAL EXAMPLE 2 Process for Producing(4S)-N-benzyloxycarbonyl-4-phenylthiomethyloxazolidine-5-on

(2S)-2-benzyloxycarbonylamino-3-phenylthiopropionic acid 5.00 g),paraformaldehyde (1.21 g) and p-toluenesulfonic acid monohydrate (0.15g) were added to benzene (50 ml), and they were stirred under heatingand reflux for 1.5 hours. The reaction mixture was cooled to roomtemperature and washed with a saturated aqueous sodium hydrogencarbonatesolution and saturated aqueous sodium chloride solution. The obtainedtoluene layer was dried over anhydrous magnesium sulfate and thenmagnesium sulfate was removed. The solvent was evaporated under reducedpressure to obtain intended(4S)-N-benzyloxycarbonyl-4-phenylthiomethyloxazolidin-5-one (5.18 g)(yield: 100%).

1H-NMR (CDCl3, 300 MHz) δ ppm: 3.36 (d, 1H), 3.60-4.02 (m, 1H),4.50-4.64 (bs, 1H), 4.78-5.51 (m, 4H), 7.11-7.46 (m, 10H)

EXAMPLE 1 Process for Producing(4S)-N-tert-butoxycarbonyl-5-chloromethyl-5-hydroxy-4-phenylmethyloxazolidine

(4S)-N-tert-butoxycarbonyl-4-phenylmethyloxazolidin-5-one (0.34 g) andbromochloromethane (0.10 ml) were added to dehydrated tetrahydrofuran(12 ml). After cooling to −78° C., 1.53 M solution (1.03 ml) ofn-butyllithium in hexane was added to the obtained mixture, and theywere stirred for 1 hour. 10% aqueous potassium hydrogensulfate solutionwas added to the reaction mixture to terminate the reaction. Thetemperature of the reaction mixture was elevated to room temperature.After the extraction with ethyl acetate twice, the obtained ethylacetate layer was dried over anhydrous magnesium sulfate and thenmagnesium sulfate was removed. The solvent was evaporated under reducedpressure to obtain intended(4S)-N-tert-butoxycarbonyl-5-chloromethyl-5-hydroxy-4-phenylmethyloxazolidine(0.40 g) in a yield of 100%.

A part of the product was treated with 6 N hydrochloric acid to form(S)-3-amino-1-chloro-4-phenyl-2-butanone hydrochloride. According toHPLC analysis with an optically active column, the optical purity wasconfirmed to be >99% e.e.

1H-NMR (CDCl3, 300 MHz) δ ppm: 1.48 (s, 9H), 3.02 (dd, J=10.1, 13.2 Hz,1H), 3.24-3.34 (m, 3H), 3.80 (d, J=11.5 Hz, 1H), 3.93 (dd, J=4.5, 10.0Hz, 1H), 4.87 (d, J=4.7 Hz, 1H), 5.17 (bs, 1H), 7.18-7.33 (m, 5H)

[α]D20=−22.8° (c=1.0, CH2Cl2)

EXAMPLE 2 Process for Producing (S)-3-amino-1-chloro-4-phenyl-2-butanoneHydrochloride

(4S)-N-tert-butoxycarbonyl-4-phenylmethyloxazolidin-5-one (1.00 g) andbromochloromethane (0.31 ml) were added to dehydrated tetrahydrofuran(36 ml). After cooling to −78° C., 1.53 M solution (3.07 ml) ofn-butyllithium in hexane was added to the obtained mixture, and theywere stirred for 40 minutes. 6 N Hydrochloric acid was added to thereaction mixture to terminate the reaction. The temperature of thereaction mixture was elevated to room temperature. The reaction mixturewas concentrated to a half volume, stirred at 50° C. for 1 hour andcooled to room temperature. After the addition of isopropyl acetatefollowed by the extraction with water twice, the obtained aqueoussolution was analyzed by HPLC to find that intended(S)-3-amino-1-chloro-4-phenyl-2-butanone hydrochloride (0.65 g) wasobtained in a yield of 77%. According to HPLC analysis with an opticallyactive column, the optical purity of(S)-3-amino-1-chloro-4-phenyl-2-butanone hydrochloride thus obtained wasconfirmed to be >99% e.e.

For obtaining various spectral data, a part of the obtained aqueoussolution was concentrated under reduced pressure. Ethanol was added tothe concentrate. The solvent was evaporated again under reducedpressure. After the filtration, the filtrate was concentrated and thenthe product was crystallized from ethanol and tert-butyl methyl ether toobtain crystals of (3S)-3-amino-1-chloro-4-phenyl-2-butanonehydrochloride.

1H-NMR (d6-DMSO, 300 MHz) δ ppm: 3.04 (dd, J=7.1, 15.2 Hz, 1H), 3.22(dd, J=7.1, 15.2 Hz, 1H), 4.54 (t, J=7.1 Hz, 1H), 4.58 (d, J=17.3 Hz,1H), 4.70 (d, J=17.3 Hz, 1H), 7.28-7.41 (m, 5H), 8.37 (bs, 3H)

mass spectrum m/e: 198.0 (MH+)

[α]_(D) ²⁵=+30.20 (c=0.5, H₂O)

optical purity: >99.5% e.e.

EXAMPLE 3 Process for Producing(3S)-3-tert-butoxycarbonylamino-1-chloro-4-phenyl-2-butanone

Di-tert-butyl dicarbonate (1.39 g) and sodium hydrogencarbonate (0.34 g)were dissolved in 50% aqueous methanol solution (22 ml). An aqueoussolution of (3S)-3-amino-1-chloro-4-phenyl-2-butanone hydrochloride(0.94 g) was added to the obtained solution, and they were stirred at40° C. for 1.5 hours. After the extraction with ethyl acetate twice, theobtained ethyl acetate layer was dried over anhydrous magnesium sulfate.Magnesium sulfate was removed. The solvent was evaporated under reducedpressure. Crystals formed by the crystallization with ethyl acetate andhexane were taken by filtration and then dried to obtain(3S)-3-tert-butoxycarbonylamino-1-chloro-4-phenyl-2-butanone (0.84 g) ina yield of 70%.

The obtained crystals and the reaction mixture were analyzed by HPLCwith an optically active column to confirm that the product had anoptical purity of >99.5% e.e.

1H-NMR (CDCl3, 300 MHz) δ ppm: 1.41 (s, 9H), 3.00(dd, J=6.9, 13.8 Hz),3.08 (dd, J=6.9, 13.8 Hz, 1H), 3.98 (d, J=16.2 Hz, 1H), 4.17 (d, J=16.2Hz, 1H), 4.68 (q, J=6.9 Hz, 1H), 5.02 (bd, J=6.9 Hz, 1H), 7.16 (m, 2H),7.26-7.36 (m, 3H)

mass spectrum m/e: 296.1 (M−H−)

[α]_(D) ²⁵=−55.7° (c=1, EtOH)

EXAMPLE 4 Process for Producing (2S,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane

(3S)-3-tert-butoxycarbonylamino-1-chloro-4-phenyl-2-butanone (0.57 g)was added to a mixed solution of methanol (9 ml) and methylene chloride(9 ml). Sodium borohydride (92 mg) was added in portions to the obtainedmixture under cooling with ice, and they were stirred for 1 hour. Aceticacid (0.59 ml) was added to the reaction mixture to terminate thereaction. After the addition with water followed by the extraction withisopropyl acetate twice, the obtained solution in isopropyl acetate waswashed with 5% aqueous sodium hydrogencarbonate solution twice andsaturated aqueous sodium chloride solution once.

The obtained solution in isopropyl acetate was analyzed by HPLC to findthat 3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (0.57g) was obtained in a yield of 83%. The ratio of the intended (2S, 3S)compound to the isomer thereof (2R, 3S) was (2S, 3S)/(2R, 3S)=83.2:16.8.

A part of the solvent was evaporated from a part of the solution of (2S,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane inisopropyl acetate under reduced pressure. Ethyl acetate was added to theresidue, and they were heated to obtain a solution. n-Hexane was addedto the obtained solution. After the crystallization under cooling withice, crystals of (2S,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane wereobtained. The spectral data were obtained. The ratio of the intendedproduct (2S, 3S) to the isomer thereof (2R, 3S) in the obtained crystalswas as follows: (2S, 3S)/(2R, 3S)=92.3:7.7.

1H-NMR (CDCl3, 300 MHz) δ ppm: 1.37 (s, 9H), 2.85-2.98 (m, 1H), 3.00(dd, J=5.8, 13.9 Hz, 1H), 3.16 (bs, 1H), 3.59 (dd, J=11.6, 17.4 Hz, 1H),3.59-3.71 (m, 1H), 3.77-3.97 (bm, 2H), 4.57 (bs, 1H), 7.19-7.35 (m, 5H)

mass spectrum m/e: 322 (M+Na+)

[α]_(D) ²⁰=−23.6° (c=0.5, CH₂Cl₂)

EXAMPLE 5 Process for Producing(2S,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane

(2S,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane(0.40 g) and potassium carbonate (0.37 g) were added to methanol (8 ml),and they were stirred at room temperature for 6 hours. The inorganicsalt was removed from the reaction mixture by the filtration and thenthe filtrate was analyzed by HPLC to confirm that intended(2S,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (0.35 g) wasobtained in a yield of 100%. The filtrate was concentrated under reducedpressure. Water was added to the residue. After the extraction withmethylene chloride, the obtained methylene chloride layer was washedwith 20% aqueous citric acid solution. The solvent was evaporated underreduced pressure. Ethyl acetate (2 ml) was added to the residue and theywere heated to obtain a solution, which was cooled to room temperatureto conduct the crystallization. n-Hexane (4 ml) was added thereto andthey were stirred under cooling on ice. The crystals were separated anddried to obtain intended crystals of(2S,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (0.30 g) ina yield of 85%.

1H-NMR (CDCl3, 300 MHz) δ ppm: 1.38 (s, 9H), 2.73-2.81 (m, 2H),2.84-3.01 (m, 3H), 3.69 (bs, 1H), 4.54 (d, J=8.2 Hz, 1H), 7.21-7.31 (m,5H

13C-NMR (CDCl3,75 MHz) δ ppm: 28.3, 37.6, 46.8, 52.6, 53.2, 79.6, 126.6,128.5, 129.4, 136.7, 155.2

mass spectrum m/e: 286 (M+Na+)

[α]_(D) ²⁰=−15.4° (c=2.2, CH₂Cl₂)

EXAMPLE 6 Process for Producing(3S)-3-benzyloxycarbonylamino-1-chloro-4-phenyl-2-butanone

(4S)-N-benzyloxycarbonyl-2-(p-methoxyphenyl)-4-phenylmethyloxazolidin-5-one(Tetrahedron Lett. 1995, 36, 42, 7761) (700 mg) and bromochloromethane(0.142 ml) were added to dehydrated tetrahydrofuran (16.8 ml), and theywere cooled to −78° C. 1.54 Mn-butyllithium solution (1.42 ml) in hexanewas added to the obtained mixture, and they were stirred for 33 minutes.5% aqueous potassium hydrogensulfate solution was added to the reactionmixture to terminate the reaction. After the extraction with ethylacetate at room temperature twice followed by drying over anhydrousmagnesium sulfate, magnesium sulfate was removed. The obtained solutionin ethyl acetate was analyzed by HPLC to find that(3S)-3-benzyloxycarbonylamino-1-chloro-4-phenyl-2-butanone (347 mg) wasobtained in a yield of 62%.

EXAMPLE 7 Process for Producing(3S)-3-tert-butoxycarbonylamino-1-chloro-4-phenyl-2-butanone

Di-tert-butyl dicarbonate (4.64 g) and triethylamine (5.28 ml) weredissolved in toluene (81.9 ml). An aqueous solution (45.60 g) of(3S)-3-amino-1-chloro-4-phenyl-2-butanone hydrochloride (3.83 g) wasadded dropwise to the obtained solution for a period of 10 minutes.After stirring at room temperature for 1 hour, the reaction mixture wato 40° C. and the reaction was cnoducted for additional 1 hour. Thereaction mixture was cooled to room temperature, and the aqueous layerwas separated. The resultant toluene layer was washed with 2 Nhydrochloric acid and saturated aqueous sodium chloride solution andthen dried over anhydrous magnesium sulfate. Magnesium sulfate wasremoved. The obtained toluene layer was analyzed by HPLC to find that(3S)-3-tert-butoxycarbonylamino-1-chloro-4-phenyl-2-butanone (3.94 g)was obtained in a yield of 81%. The solvent was evaporated under reducedpressure, and n-hexane and 2-propanol were added to the residue. Theywere heated to 50° C. to obtain a homogeneous solution, which was cooledto room temperature, stirred for 1 hour, then cooled to 5° C. andstirred for 1 hour. Crystals thus formed were taken by the filtrationand then dried to obtain(3S)-3-tert-butoxycarbonylamino-1-chloro-4-phenyl-2-butanone (2.98 g) ina crystallization rate of 75%.

EXAMPLE 8 Process for Producing(3S)-3-benzyloxycarbonylamino-1-chloro-4-phenyl-2-butanone

(3S)-3-Amino-1-chloro-4-phenyl-2-butanone hydrochloride (100 mg) wasdissolved in water (4.3 ml). A solution (5.3 ml) of benzyl chloroformate(0.794 ml) in toluene was added to the obtained solution. Further, anaqueous solution (1.0 ml) of sodium hydrogencarbonate (71.9 mg) wasadded dropwise to the obtained mixture. They were stirred at roomtemperature for 50 minutes to conduct the reaction and then the aqueouslayer was separated. The obtained toluene layer was analyzed by HPLC tofind that (3S)-3-benzyloxycarbonylamino-1-chloro-4-phenyl-2-butanone(118 mg) was obtained in a yield of 83%.

EXAMPLE 9 Process for Producing(3S)-3-methoxycarbonylamino-1-chloro-4-phenyl-2-butanone

(3S)-3-Amino-1-chloro-4-phenyl-2-butanone hydrochloride (2.0 g) wasdissolved in water (34 ml). A solution (50 ml) of methyl chloroformate(0.858 ml) in toluene was added to the obtained solution. Further, anaqueous solution (15 ml) of sodium hydrogencarbonate (1.44 g) was addeddropwise to the obtained mixture. They were stirred at room temperaturefor 1 hour to conduct the reaction. After the extraction with toluenetwice and with ethyl acetate twice, the organic layers were combinedtogether. The solvents were evaporated under reduced pressure. n-Hexaneand 2-propanol were added to the residue. The obtained mixture washeated to 50° C. to obtain a homogeneous solution, which was cooled to10° C. to form crystals. The crystals were taken by the filtration,washed with cold 2-propanol (6 ml) and then dried to obtain(3S)-3-methoxycarbonylamino-1-chloro-4-phenyl-2-butanone (1.70 g) in ayield of 78%.

¹H-NMR (CDCl₃) δ ppm: 2.97-3.14 (m, 2H), 3.66 (s, 3H), 3.98 (d, J=16.0Hz, 1H), 4.15 (d, J=16.0 Hz, 1H), 4.75 (q, J=7.2 Hz, 1H), 5.21 (bd, 1H),7.12-7.18 (m, 2H), 7.23-7.37 (m, 3H)

EXAMPLE 10 Process for Producing(2S,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane

Ethyl acetate (4.2 ml) and ethanol (16.7 ml) were added to(3S)-3-tert-butoxycarbonylamino-1-chloro-4-phenyl-2-butanone (2.08 g).Sodium borohydride (133 mg) was added in portions to the obtainedmixture at −10° C., and they were stirred for 1 hour 40 minutes. Aceticacid (0.40 ml) was added to the reaction mixture to terminate thereaction. The reaction mixture was slowly heated to 60° C. for theduration of 1 hour and then stirred at 60° C. for 30 minutes. Thereaction mixture was slowly cooled to −10° C. for the duration of 1 hour50 minutes and then stirred at −10° C. for 6 hours. The crystals thusformed were taken by the filtration, washed with 0° C. water and driedunder reduced pressure to obtain intended(2S,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane(1.52 g).

EXAMPLE 11 Process for Producing(2S,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane

(2S,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-henylbutane(3.57 g) was added to a mixed solution (35.7 ml) of ethanol and water(97:3), and they were stirred at 27° C. for 22 hours and then at 33° C.for 4 hours. 11.3% aqueous citric acid solution (40.3 g) was added tothe obtained mixture, and they were cooled to −10° C. The crystals thusformed were taken by the filtration, washed with water (35.7 ml) anddried under reduced pressure to obtain intended(2S,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (2.88 g) ina yield of 95%.

EXAMPLE 12 Process for Producing(2S,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane

2-Propanol (2.4 ml) was added to(2S,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane(300 mg). After cooling to 4° C., 4 mol/l aqueous sodium hydroxidesolution (0.375 ml) and water (0.225 ml) were added to the obtainedmixture, and they were stirred at 4° C. for 7 hours. 13.7% aqueouscitric acid solution (695 mg) was added to the reaction mixture. Afterthe extraction with tert-butyl methyl ether, the obtained organic layerwas washed with water and analyzed by HPLC to find that intended(2S,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (230 mg)wasobtained in an yield of 87%.

According to the present invention, α-aminohalomethyl ketones,N-protected α-aminohalomethyl ketones and related substances can beefficiently produced at a low cost from N-protected α-amino acids orα-amino acids. Thus, various compounds useful as intermediates formedicines can be produced. Because the optical activity can be kept, theprocess of the present invention is particularly suitable for producingintermediates of medicines having structures derived from opticallyactive amino acids.

1. A process for producing N-protected β-aminoalcohols of followingformula (8), or a salt thereof:

wherein A represents an unsubstituted or substituted alkyl group having1 to 10 carbon atoms, aryl group having 6 to 15 carbon atoms or aralkylgroup having 7 to 20 carbon atoms, an unsubstituted or substituted alkylgroup having 1 to 10 carbon atoms which contains a hetero atom in thecarbon skeleton, an aryl group having 6 to 15 carbon atoms whichcontains a hetero atom in the carbon skeleton, or an aralkyl grouphaving 7 to 20 carbon atoms which contains a hetero atom in the carbonskeleton; B¹ represents a protecting group for the amino group; and Xrepresents a halogen atom, which comprises producing an N-protectedα-aminohalomethyl ketone of formula (3), or a salt thereof,

wherein A, B¹, and X are as defined above, and then reducing thisketone, wherein said producing an N-protected α-aminohalomethyl ketoneof formula (3) comprises: reacting a 3-oxazolidin-5-one derivative ofthe following (1):

wherein R represents an unsubstituted or substituted aryl group or loweralkyl group, or a hydrogen atom, and A and B¹ are as defined above; witha halomethyl lithium to produce a reaction product; and then treatingthe reaction product with an acid.
 2. A process for producingN-protected β-aminoepoxides of following formula (9):

wherein A represents an unsubstituted or substituted alkyl group having1 to 10 carbon atoms, aryl group having 6 to 15 carbon atoms or aralkylgroup having 7 to 20 carbon atoms, an unsubstituted or substituted alkylgroup having 1 to 10 carbon atoms which contains a hetero atom in thecarbon skeleton, an aryl group having 6 to 15 carbon atoms whichcontains a hetero atom in the carbon skeleton, or an aralkyl grouphaving 7 to 20 carbon atoms which contains a hetero atom in the carbonskeleton; and B¹ represents a protecting group for the amino group,which comprises producing an N-protected β-amino alcohol of formula (8)by the process of claim 1, and then treating this alcohol with a base.3. A process for producing N-protected β-aminoalcohols of followingformula (11):

wherein A represents an unsubstituted or substituted alkyl group having1 to 10 carbon atoms, aryl group having 6 to 15 carbon atoms or aralkylgroup having 7 to 20 carbon atoms, an unsubstituted or substituted alkylgroup having 1 to 10 carbon atoms which contains a hetero atom in thecarbon skeleton, an aryl group having 6 to 15 carbon atoms whichcontains a hetero atom in the carbon skeleton, or an aralkyl grouphaving 7 to 20 carbon atoms which contains a hetero atom in the carbonskeleton; B² represents a protecting group for the amino group; and Xrepresents a halogen atom, which comprises producing an N-protectedα-aminohalomethyl ketone of formula (10):

wherein A, B², and X are as defined above, and then reducing thisketone, wherein said producing N-protected α-aminohalomethyl ketone ofthe following formula (10) comprises: producing an α-aminohalomethylketone of the formula (4):

wherein A and X are as defined above, or a salt thereof, by reacting a3-oxazolidin-5-one derivative of the following formula (1):

wherein R represents an unsubstituted or substituted aryl group or loweralkyl group, or a hydrogen atom, B¹ represents a protecting group forthe amino group, and A is as defined above with a halomethyl lithium toproduce a reaction product; treating the reaction product with an acid;and then protecting the amino group thereof.
 4. A process for producingN-protected β-aminoepoxides of following formula (12):

wherein A represents an unsubstituted or substituted alkyl group having1 to 10 carbon atoms aryl group having 6 to 15 carbon atoms or aralkylgroup, having 7 to 20 carbon atoms, an unsubstituted or substitutedalkyl group having 1 to 10 carbon atoms which contains a hetero atom inthe carbon skeleton, an aryl group having 6 to 15 carbon atoms whichcontains a hetero atom in the carbon skeleton, or an aralkyl grouphaving 7 to 20 carbon atoms which contains a hetero atom in the carbonskeleton; and B² represents a protecting group for the amino group, bywhich comprises producing an N-protected β-amino alcohol of formula (11)by the process of claim 3, and then treating this alcohol with a base.5. A process for producing β-aminoalcohols of following formula (13), ora salt thereof:

wherein A represents an unsubstituted or substituted alkyl group having1 to 10 carbon atoms, aryl group having 6 to 15 carbon atoms or aralkylgroup having 7 to 20 carbon atoms, an unsubstituted or substituted alkylgroup having 1 to 10 carbon atoms which contains a hetero atom in thecarbon skeleton, an aryl group having 6 to 15 carbon atoms whichcontains a hetero atom in the carbon skeleton, or an aralkyl grouphaving 7 to 20 carbon atoms which contains a hetero atom in the carbonskeleton; and X represents a halogen atom, or salts thereof, by whichcomprises producing an α-aminohalomethyl ketone of formula (4):

wherein A and X are as defined above, or a salt thereof, and thenreducing this ketone, wherein said producing an α-aminohalomethyl ketoneof formula (4) comprises: reaction a 3-oxazolidin-5-one derivative ofthe following formula (1):

wherein R represents an unsubstituted or substituted aryl group or loweralkyl group, or a hydrogen atom, and A and B¹ are as defined above witha halomethyl lithium to produce a reaction product; and then treatingthe reaction product with an acid.
 6. A process for producingN-protected β-aminoalcohols of following formula (14):

wherein A represents an unsubstituted or substituted alkyl group having1 to 10 carbon atoms, aryl group having 6 to 15 carbon atoms or aralkylgroup having 7 to 20 carbon atoms, an unsubstituted or substituted alkylgroup having 1 to 10 carbon atoms which contains a hetero atom in thecarbon skeleton, an aryl group having 6 to 15 carbon atoms whichcontains a hetero atom in the carbon skeleton, or an aralkyl grouphaving 7 to 20 carbon atoms which contains a hetero atom in the carbonskeleton; B³ represents a protecting group for the amino group; and Xrepresents a halogen atom, which comprises producing a β-aminoalcohol offormula (13) or a salt thereof by the process of claim 5, and thenprotecting the amino group thereof with a protecting group.
 7. A processfor producing N-protected β-aminoepoxides of following formula (15):

wherein A represents an unsubstituted or substituted alkyl group having1 to 10 carbon atoms, aryl group having 6 to 15 carbon atoms or aralkylgroup having 7 to 20 carbon atoms, an unsubstituted or substituted alkylgroup having 1 to 10 carbon atoms which contains a hetero atom in thecarbon skeleton, an aryl group having 6 to 15 carbon atoms whichcontains a hetero atom in the carbon skeleton, or an aralkyl grouphaving 7 to 20 carbon atoms which contains a hetero atom in the carbonskeleton; and B³ represents a protecting group for the amino group, bywhich comprises producing an N-protected β-amino alcohol of formula (14)by the process of claim 6, and then treating this alcohol with a base.